Poly ADP- ribose signaling is dysregulated in Huntington disease

• 成果类型: Article
• 署名作者: Maiuri, Tamara; Bazan, Carlos Barba; Harding, Rachel J.; Begeja, Nola; Kam, Tae-In; Byrne, Lauren M.; Rodrigues, Filipe B.; Warner, Monica M.; Neuman, Kaitlyn; Mansoor, Muqtasid; Badiee, Mohsen; Dasovich, Morgan; Wang, Keona; Thompson, Leslie M.; Leung, Anthony K. L.; Andres, Sara N.; Wild, Edward J.; Dawson, Ted M.; Dawson, Valina L.; Arrowsmith, Cheryl H.; Truant, Ray
• 署名单位: McMaster University; University of Toronto; University of Toronto; Structural Genomics Consortium; University of Toronto; Johns Hopkins University; Johns Hopkins University; University of London; University College London; McMaster University; Johns Hopkins University; Johns Hopkins Bloomberg School of Public Health; University of California System; University of California Irvine; University of California System; University of California Irvine; Johns Hopkins University; Johns Hopkins University; Johns Hopkins University; Johns Hopkins University; Johns Hopkins University; Johns Hopkins University; University of Toronto; University Health Network Toronto; Princess Margaret Cancer Centre; University of Toronto
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9063
• DOI: 10.1073/pnas.2318098121
• 发表日期: 2024-10-01
• 关键词: proteome-wide identification; dna-damage; poly(adp-ribose) polymerase; repair pathways; n-17 domain; nuclear; onset; ataxia; inhibitors; Mutation

摘要

Huntington disease (HD) is a genetic neurodegenerative disease caused by cytosine, adenine, guanine (CAG) expansion in the Huntingtin (HTT) gene, translating to an expanded polyglutamine tract in the HTT protein. Age at disease onset correlates to CAG repeat length but varies by decades between individuals with identical repeat lengths. Genome-wide association studies link HD modification to DNA repair and mitochondrial health pathways. Clinical studies show elevated DNA damage in HD, even at the premanifest stage. A major DNA repair node influencing neurodegenerative disease is the PARP pathway. Accumulation of poly adenosine diphosphate (ADP)- ribose (PAR) has been implicated in Alzheimer and Parkinson diseases, as well as cerebellar ataxia. We report that HD mutation carriers have lower cerebrospinal fluid PAR levels than healthy controls, starting at the premanifest stage. Human HD induced pluripotent stem cell- derived neurons and patient- derived fibroblasts have diminished PAR response in the context of elevated DNA damage. We have defined a PAR- binding motif in HTT, detected HTT complexed with PARylated proteins in human cells during stress, and localized HTT to mitotic chromosomes upon inhibition of PAR degradation. Direct HTT PAR binding was measured by fluorescence polarization and visualized by atomic force microscopy at the single molecule level. While wild- type and mutant HTT did not differ in their PAR binding ability, purified wild- type HTT protein increased in vitro PARP1 activity while mutant HTT did not. These results provide insight into an early molecular mechanism of HD, suggesting possible targets for the design of early preventive therapies.